We have found that the covalent bonding of poly(L-lysine) (PLL), MW 6,700, to horseradish peroxidase (HRP) enhances more than 100-fold the cellular uptake of active enzyme. This finding will be developed in two ways: 1) by using the same transport marker to facilitate the cellular penetration of other enzymes and other biologically active proteins; 2) by using larger PLL's as transport carrier for small molecules, especially cancer chemotherapeutic agents, which are not adequately transported into cells. The enzymes to be conjugated are lysosomal enzymes involved in storage diseases, especially beta-glucuronidase and beta-glucosidase. Diphtheria toxin will exemplify a protein with strong biological activity. The cellular uptake of its PLL-conjugate will be assessed by measuring its inhibitory effect on protein synthesis in mouse cells which lack the toxin receptor. The small molecules which will be conjugated to a backbone of PLL are methotrexate, daunorubicin and nucleotide analogs corresponding to 6-mercaptopurine, cytosine arabinoside, dideoxyadenosine and dideoxythymidine. It is postulated that PLL-methotrexate will overcome resistance due to inadequate methotrexate transport. It is postulated that PLL-nucleotide-analogs will overcome drug resistance due to the lack of phosphoribosylation or phosphorylation or to the excess deamination of the conventional analogs. PLL-conjugates of physiological nucleotides will be used to test if they can counteract excessive doses of conventional analogs and thus be considered for "rescue therapy." PLL-HRP with optimal transport properties will be made available for neuro-anatomical investigations. They will also be used to study the ultrastructure of protein uptake using conventional and high voltage electron microscopy as well as freeze fracture techniques. The new data obtained will be used as tools to compare membrane structure and function of malignant versus nonmalignant cells in the search for critical differences related to the abnormal growth behavior of malignant cells.